Monocytes/macrophages demonstrate topographical and functional specificity directed by the micro-anatomic milieu suggesting a key role of extracellular factors in determining cell differentiation and functional activity. Interactions with the microenvironment results in macrophage activation, production of numerous soluble signaling molecules including pro- and anti-inflammatory cytokines, and growth and regulatory factors. Following injury, macrophages and monocytes are recruited and become key mediators of inflammation, tissue repair, and cellular debris clearance. However, dysfunctional control of the magnitude and duration of inflammation can result in damage to the host, such as in auto-immunity, numerous destructive and degenerative diseases (rheumatoid arthritis and Alzheimer's disease), non-healing ulcers, and infections such as leprosy and leishmaniasis. A hallmark of excess inflammation is damage to the surrounding tissue. However, the factors and underlying mechanisms that govern the function of macrophages in the context of inflammation and tissue destruction remain incompletely understood.